Direct Catalytic Enantio- and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates**

A catalytic asymmetric aldol addition/cyclization reaction of unactivated ketones with isocyanoacetate pronucleophiles has been developed. A quinine-derived aminophosphine precatalyst and silver oxide were found to be an effective binary catalyst system and promoted the reaction to afford chiral oxazolines possessing a fully substituted stereocenter with good diastereoselectivities and excellent enantioselectivities.

The aldol reaction is one of the most powerful methods for the construction of b-hydroxy carbonyl compounds. [1] The importance of these building blocks,c ontained in aw ide variety of biologically relevant compounds,has promoted the development of several catalytic asymmetric methods for their production. [2] However, despite enormous progress in the aldol addition arena, its application to the synthesis of tertiary alcohols still remains am ajor challenge,p rincipally owing to al ack of reactivity and the fact that the differentiation of the enantiotopic faces is more difficult with ketone electrophiles than with the corresponding aldehydes. Furthermore,d eleterious side reactions,s uch as retro-aldol reactions,c an predominate when ak etone moiety is involved. [3] Although af ew catalytic asymmetric aldol reactions with unactivated ketones have been reported, [4] the development of new and efficient catalytic asymmetric methods to access chiral tertiary alcohols remains an important goal in modern asymmetric catalysis. [5] Along these lines,w er ecognized that the catalytic asymmetric ketone aldol reaction of isocyanoacetate pronucleophiles [6] could be as ynthetically powerful approach.
Isocyanoacetate ester addition reactions to carbonyl [7] or imine electrophiles [8,9] directly afford the respective oxazoline or imidazoline heterocycles,which can be ring-opened under mild hydrolytic conditions to yield b-substituted a-amino acids.A lthough the catalytic asymmetric version of this reaction has been widely studied using aldehydes, [7] to date, no enantioselective example using unactivated ketones has been reported despite its potential to provide an elegant asymmetric route to a-amino acid derivatives possessing ac hiral tertiary alcohol in the b-position (Scheme 1). [10] In ar elated study,t he asymmetric aldol addition reaction of isothiocyanato esters and unactivated ketones,w hich afforded oxazolidinethione products with af ully substituted b-stereocenter,w as described. [11] Forpromoting and controlling various addition reactions, our group has developed an effective binary catalyst system comprising a" soft" metal ion, such as as ilver (I) ion, and ac inchona-derived aminophosphine precatalyst of type 1. This system promotes the highly diastereo-and enantioselective aldol reaction of isocyanoacetates with aldehydes, [7l] and Mannich reactions of aldimines [8e] and ketimines. [9a] The precatalyst is equipped with Brønsted basic and Lewis basic sites and also possesses ahydrogen-bond donor group located in the proximity of the chiral pocket that is created by the cinchona scaffold (Scheme 1). In conjunction with Ag I ions, these features provide remarkable catalytic activity in reactions of isocyanoacetate pronucleophiles and accordingly prompted us to address the challenging enantioselective aldol reaction of unactivated ketones.
Subsequently,t he effect of lowering the catalyst loading was studied (Table 2). trans-Oxazoline 4a was obtained with marginally lower levels of enantioselectivity when the loading was reduced to 5a nd 1mol %o f1a while maintaining ap recatalyst/metal ratio of 2:1r atio (entries 2a nd 3). However,d iastereo-and enantioselectivities that are comparable to the best values reported in Table 1w ere achieved when precatalyst 1a and Ag I were employed in a1:1 ratio at aprecatalyst loading of 5mol %( entry 1).
[c] The enantiomeric ratios (e.r.) were determined by HPLC analysis on achiral stationary phase.
As the stereochemical outcome favored the production of the trans-configured oxazoline product, and as alkyl groups larger than amethyl group were well tolerated in the ketone aldol reaction, our reaction could be applied to the synthesis of oxazoline-fused g-a nd d-lactam derivatives.T herefore, azides 3r and 3s were subjected to the standard reaction conditions,a nd pleasingly,o xazolines 4u and 4v were afforded in good yield and with excellent enantioselectivities. Subsequently,u nder standard Staudinger conditions,t hese oxazolines were transformed into the target lactam products 5a and 5b with high yields in as traightforward manner without compromising stereochemical integrity (Scheme 2).
To demonstrate further synthetic utility whilst expanding our knowledge on the hydrolytic manipulation of oxazoline heterocycles, [13] we subsequently explored the conversion of oxazolines 4 into the corresponding amino acid derivatives under different reaction conditions.T he hydrolysis of oxazoline 4e using catalytic amounts of HCl afforded the corresponding N-formyl derivative 6 in quantitative yield (Scheme 3a). Similarly,m ethanolysis of 4e led to the corresponding b-hydroxy-a-amino acid tertbutyl ester 7 under mild conditions (Scheme 3b). These transformations highlight the ability of our method to afford protected serine derivatives with adoubly substituted b-position. Furthermore,treatment of 7 with thiophosgene under basic conditions furnished crystalline oxazolidinethione 8 (Scheme 3c); [14] its absolute and relative stereochemical configurations were determined by single-crystal Xray diffraction, and those of the other oxazolines (4a-4v)w ere assigned by analogy.
Based on previous reports [9b, 15] and on the known absolute stereochemical configuration of oxazoline products 4,atransition-state model rationalizing the stereochemical outcome of the ketone aldol reaction between 3a and 2a in the presence of precatalyst 1a and silver oxide is proposed in Scheme 4. In the enantiodetermining carbon-carbon bond-forming step,t he phosphorus and amide nitrogen atoms of 1a,the oxygen atom of ketone 3a,a nd the terminal carbon atom of the isonitrile coordinate to asilver(I) ion in atetrahedral arrangement. Additional transition-state stabilization is provided through hydrogen bonding of the protonated quinuclidine to the coordinated ketone oxygen atom. Importantly,this interaction creates aw ell-defined chiral pocket that can readily differentiate the enantiotopic faces of the bound ketone;u nfavorable steric interactions force the aryl group away from the quinuclidine,and attack of the enolate occurs preferentially to the Re face.
In conclusion, we have developed the first highly enantioand diastereoselective aldol addition/cyclization reaction of isocyanoacetate esters with unactivated prochiral ketones to afford functionalized oxazolines with af ully substituted stereogenic center at the b-carbon atom. Ther eaction is

Angewandte
Chemie efficient and broad in scope and effectively promoted by ab inary catalyst system that consists of ac inchona-derived aminophosphine precatalyst and silver oxide.Incombination with hydrolytic transformations of the oxazoline heterocycles, this method enables the transformation of simple ketones into the corresponding amino acid derivatives possessing atertiary alcohol in the b-position. Further studies towards the discovery and application of new asymmetric isocyanoacetate addition reactions are ongoing in our laboratories,a nd the results will be reported in due course.